First Assessment in Humans of the Safety, Tolerability, Pharmacokinetics, and Ex Vivo Pharmacodynamic Antimalarial Activity of the New Artemisinin Derivative Artemisone

Abstract

In preclinical studies, artemisone (BAY 44-9585), a new artemisinin derivative, was shown to possess enhanced efficacy over artesunate, and it does not possess the neurotoxicity characteristic of the current artemisinins. In a phase I program with double-blind, randomized, placebo-controlled, single and multiple ascending oral-dose studies, we evaluated the safety, tolerability, pharmacokinetics, and ex vivo pharmacodynamic antimalarial activity of artemisone. Single doses (10, 20, 30, 40, and 80 mg) and multiple doses (40 and 80 mg daily for 3 days) of artemisone were administered orally to healthy subjects. Plasma concentrations of artemisone and its metabolites were measured by liquid chromatography/tandem mass spectrometry (LC/MS-MS). Artemisone was well tolerated, with no serious adverse events and no clinically relevant changes in laboratory and vital parameters. The pharmacokinetics of artemisone over the 10-to 80-mg range demonstrated dose linearity. After the single 80-mg dose, artemisone had a geometric mean maximum concentration of 140.2 ng/ml (range, 86.6 to 391.0), a short elimination half-life (t 1/2 ) of 2.79 h (range, 1.56 to 4.88), a high oral clearance of 284.1 liters/h (range, 106.7 to 546.7), and a large volume of distribution of 14.50 liters/kg (range, 3.21 to 51.58). Due to artemisone's short t 1/2 , its pharmacokinetics were comparable after single and multiple dosing. Plasma samples taken after multiple dosing showed marked ex vivo pharmacodynamic antimalarial activities against two multidrug-resistant Plasmodium falciparum lines. Artemisone equivalent concentrations measured by bioassay revealed higher activity than artemisone measured by LC/MS-MS, confirming the presence of active metabolites. Comparable to those of other artemisinin's, artemisone's t 1/2 is well suited for artemisinin-based combination therapy for the treatment of P. falciparum malaria.Artemisinin and its derivatives, artesunate, artemether, and dihydroartemisinin, are the most potent and rapidly acting antimalarial drugs available today (1, 33). They have very high parasite kill rates with a broad stage specificity of antimalarial action and produce a faster clinical and parasitological response than any other class of antimalarial drug (24,32,33). However, a therapeutic drawback of the artemisinins is the high recrudescence rates associated with monotherapy (6). For artemisinins to be effective when given alone, they must be administered for 7 days, but adherence to 7-day regimens may be poor in patients (34).The latest therapeutic approach to combat both malaria infections and the development of drug resistance has been the use of artemisinin-based combination therapy (ACT) administered over 3 days (1,23,24,34). However, 3-day regimens with the rapidly eliminated artemisinins are usually not curative unless they are given in combination with a slowly eliminated drug, such as mefloquine (34). Although the artemisinins have become the drug of choice for the treatment of multidrug-resistant Plasmodium falciparum malari...

Synthesis of Artemiside and Its Effects in Combination with Conventional Drugs against Severe Murine Malaria

“…1a). Artemisone is highly effective against P. falciparum in monkeys and has been used in phase IIa clinical trials for nonsevere malaria in humans (34). Recent work also indicates the marked superiority of artemiside over artemisone in both in vitro and in vivo studies involving the apicomplexan parasite Toxoplasma gondii (12).…”

In vitro study of the anti-cancer effects of artemisone alone or in combination with other chemotherapeutic agents

“…It is significantly more active against Plasmodium falciparum than other derivatives [4,8,9], has almost negligible toxicity [10], and is prepared in a three step process from the parent ART.…”

Assessment of the Induction of Dormant Ring Stages in Plasmodium falciparum Parasites by Artemisone and Artemisone Entrapped in Pheroid Vesicles In Vitro

“…Artemisone (AMS), a new derivative, has potent antiplasmodial activity, good oral bioavailability, and metabolic stability (5) and is well tolerated in humans (6), with an effective curative dose approximately one-third that of artesunate (7). However, use of artemisone alone, as with the other artemisinins, also leads to recrudescence in nonhuman primates (8).…”

“…Artemisone and its metabolite M1 were obtained from the Hong Kong University of Science and Technology. The active M1 metabolite is formed via dehydrogenation in the thiomorpholine-dioxide moiety of artemisone (5,6). The artemisone-entrapped Pheroid vesicles (AMS-Phe) were prepared by adding 30 mM artemisone to a pro-Pheroid formulation (i.e., oil phase only) containing 4.9% polyethylene glycol 400 (PEG-400) instead of 20%, vitamin F ethyl ester, PEGylated ricinoleic acid (Kolliphor), and ␣-tocopherol as previously described (23).…”